Exposure to ozone (O3) continues as a significant public health concern especially with regards to sensitive populations. However, responses to a given exposure demonstrate marked heterogeneity with respect to age, anatomic site, species, and exposure history. The respiratory tract surfaces are covered by an aqueous layer (epithelial lining fluid; ELF) that inhaled gases first encounter and is a complex mixture that contains significant concentrations of small molecular weight antioxidants, principally ascorbic acid (AH2), glutathione (GSH), and uric acid (UA). The standard paradigm proposes that ELF antioxidants provide a protective screen against the injurious effect of inhaled O3. Nonetheless, compelling evidence suggests that reactions between O3 and ELF constituents are critical to the induction of exposure-related cell injury. Due to the unique absorption properties of O3, the endogenous pools and regulation of ELF constituents will dictate the profile of bioactive/cytotoxic species generated during exposure. We hypothesize that the spatial distribution, magnitude, and temporal pattern of biological responses to O3 exposure are dependent on the extracellular chemistry occurring between O3 and constituents of the ELF. As part of the overall Program Project, Project 1 will characterize how surface interactions function to dictate the local dose. Both the surface chemistry and the ELF pharmacodynamics, in combination with O3 flux rates, function to dictate the local dose. Our hypothesis will be addressed by four specific aims that will characterize, in nasal and pulmonary compartments, the surface chemistry and product formation; pharmacokinetics of AH2, GSH, and UA in the ELF; the spatial distribution of the local dose; and the contribution of the local dose to the expression of pathology across animal age (30 --> 189 days), exposure pattern (acute vs. episodic), and airway sensitization in the rhesus monkey model. These characterizations will provide key new insights regarding the mechanisms of differential susceptibility, how surface phenomena govern the impact of exposure in the developing lung, and the utility of the nose to serve as a sentinel for the lung. It is anticipated that these studies can be extended into the human population. The project will facilitate the program as a whole and directly interact with all the other projects and cores.